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Biomedical subjects

S St-Pierre

Publications and source records attributed to S St-Pierre.

At least 55 records · Page 3Linked to original sources
PubMed1995

Relaxant effects of pituitary adenylate cyclase activating polypeptide (PACAP) on epithelium-intact and -denuded guinea-pig trachea: a comparison with vasoactive intestinal peptide (VIP).

The effect of pituitary adenylate cyclase activating peptide (PACAP 1-27) was examined on epithelium-intact and -denuded guinea-pig tracheal strips (GPT) and compared to vasoactive intestinal peptide (VIP) and salbutamol. PACAP (10(-11)-10(-8) moles) induced dose-dependent relaxations of the basal tone of both epithelium-intact and -denuded GPT. PACAP was approximately three times less potent than either VIP or salbutamol in relaxing epithelium-intact GPT. The relaxant effects of both peptides and salbutamol were markedly attenuated following removal of the epithelial layer. L-NAME (10(-4) M), a nitric oxide synthase inhibitor, did not affect the responses induced by either PACAP or VIP demonstrating that the relaxant effect is independent of nitric oxide synthesis. Phosphoramidon (5 x 10(-6) M) potentiated the relaxant responses of epithelium-intact GPT to both PACAP and VIP but did not affect the responses of epithelium-denuded GPT. PACAP and VIP also induced relaxations of the guinea-pig upper bronchus. In addition, PACAP (10(-6) M), as well as VIP, significantly inhibited the release of TxB2 induced by LTD4 (10(-7) M) from chopped guinea-pig lung suggesting that this newly isolated peptide, which has 68% homology with VIP, may possess anti-inflammatory action in the lung.

Adrenergic beta-Agonists↗
PubMed1995

Structure-function studies of motilin analogues.

Over 100 motilin fragments and analogues, including monosubstituted C-terminal-deleted analogues, conformationally restricted analogues, analogues with peptide bond isoteres (CH2-NH), and N-terminal fragments adjunct to an amphiphilic helix, were synthesized by solid-phase methodology, purified by reverse-phase HPLC, and assayed in vitro in a muscle strip bioassay (rabbit duodenum) and in a radioligand binding assay on crude membrane extracts from smooth muscle (rabbit antrum). The data suggest the existence of three distinct regions involved in the interaction of motilin with its receptor: the N-terminal region (amino acids 1-7) constitutes the minimal basic unit of binding and activity; the transition region (amino acidsa 8-9) links the N-terminal and C-terminal regions; and the C-terminal region (amino acids 10-22) forms an alpha-helix that stabilizes the interaction of the N-terminal residues at the active site.

Amino Acid Sequence↗
PubMed1995

Structure-activity analysis of the motor effects of neuropeptide Y.

The purpose of the present study was to examine structure-activity relationships for three known motor effects of neuropeptide Y (NPY): decreased spontaneous activity, enhancement of muscle tone, and catalepsy. Various NPY fragments and structural analogues were synthesized and administered intracerebroventricularly in several doses (2.5-160 micrograms); their effects on these three motor variables were evaluated and compared. Globally, results indicate that the C-terminal portion of the peptide is responsible for the three motor effects of NPY. However, the distributions of potencies of the various fragments and analogues for each effect were clearly different, suggesting that the putative receptors mediating each motor effect are pharmacologically different. The findings of the present work are discussed in relation to those obtained in previous structure-activity studies.

Animals↗
PubMed1995

Mapping of hypothalamic sites involved in the effects of NPY on body temperature and food intake.

The objective of the present study was to identify hypothalamic sites that might be implicated in the effects of neuropeptide Y (NPY) on both body temperature and food intake. For this purpose, the effects of direct microinjections of NPY in several doses (0.156-20 micrograms) into discrete hypothalamic nuclei on body temperature were examined in rats. To examine specificity of effects, food consumption of animals following injections was also measured. Results indicate that the influence of NPY on body temperature varies with the hypothalamic region where the peptide is administered. NPY had no effect on temperature after administration into the ventromedial (VMH) and the perifornical hypothalamus (PeF). However, a significant hypothermia was seen following administration into the preoptic (POA) and arcuate nucleus (Arc), and hyperthermia was seen after injection into the paraventricular nucleus (PVN). Finally, a biphasic effect was observed after injection into the lateral hypothalamus (LH): hyperthermia with relatively small doses and hypothermia with higher doses. Similar effects were obtained when administered into the third ventricle (3V) but in an inverted dose-related fashion: hypothermia at low and hyperthermia at higher doses. For feeding, NPY consistently increased food intake in all regions examined, with the strongest effect obtained after administration into the PeF. The present results clearly dissociate the effects of NPY on food intake and body temperature, and demonstrate that these effects are related to specific hypothalamic nuclei.

Animals↗
PubMed1995

Effects of NPY and NPY2-36 on body temperature and food intake following administration into hypothalamic nuclei.

Our previous in vivo structure-activity studies suggested that the putative receptors mediating the effects of NPY and NPY2-36 on food intake and body temperature are pharmacologically different [17]. In the present study, we examined and compared dose-related effects of NPY and NPY2-36 on ad lib food intake and rectal temperature after administration into discrete hypothalamic nuclei of the rat. Results indicate that NPY and NPY2-36 have opposite effects on body temperature to those of NPY when injected in the preoptic area (POA): hypothermia and hyperthermia, respectively. When administered in the paraventricular nucleus (PVN), both increased body temperature. When injected into the third ventricle (3V), NPY produced a biphasic effect: hypothermia at low doses and hyperthermia at high doses. Similar effects were obtained with NPY2-36, but in an inverted dose-related fashion: hyperthermia at low and hypothermia at higher doses. In the arcuate nucleus (Arc), NPY induced a significant hypothermia whereas NPY2-36 had no effect. Finally, neither peptide affected body temperature when injected into the ventromedial (VMH) and perifornical (PeF) nuclei. Both NPY and NPY2-36 increased food intake after injection in all regions examined. In general, NPY was more potent and efficacious than NPY2-36. The present results clearly dissociate the effects of NPY on food intake and body temperature. Furthermore, the data support the hypothesis that the putative receptors underlying the effects of NPY and NPY2-36 on food intake are similar, whereas those mediating the effects on body temperature are pharmacologically different.

Animals↗
PubMed1995

Alcohol and a high-fat diet: a combination favoring overfeeding.

The effects of alcohol and dietary fat on spontaneous energy and macronutrient intakes were investigated in eight male subjects who participated in a protocol including four randomly assigned 2-d sessions during which they ate ad libitum. In each session they had free access to either high- or low-fat foods, with alcohol or a placebo. The high-fat diet was associated with a substantial increase in daily energy intake. Alcohol had no inhibitory effect on food intake and its energy content was thus associated with an additional increase in energy intake. The enhancing effects of alcohol and dietary fat on daily energy intake were additive so that overfeeding was maximal (2.8 MJ/d) under the high-fat diet+alcohol condition. To further examine the effects of alcohol on energy and macronutrient intakes, reported food intake was studied in 351 men and 360 women who had been tested in the Québec Family Study. The results showed that a high alcohol intake was associated with a high daily energy intake and had no inhibitory effect on lipid intake. In conclusion, a dietary regimen providing a high fraction of energy as alcohol and fat increases the risk for positive energy balance under free-living conditions.

Adult↗
PubMed1995

Structural characterizations of neuropeptide tyrosine (NPY) and its agonist analog [Ahx5-17]NPY by NMR and molecular modeling.

The structures of human NPY and of its centrally truncated agonist analog [Ahx5-17]NPY have been investigated in DMSO-d6 by two-dimensional NMR and by molecular modeling. For both peptides, a complete resonance assignment was achieved and a large number (more than 200) of inter-residue NOE connectivities were observed, including long-range connectivities between the N- and C-terminal ends of the chain. Molecular models were calculated using NOE constraints by distance geometry, simulated annealing and conjugate gradient energy minimization. The results indicate that both peptides are folded in the center of their chain, NPY adopting the hairpin shape, whereas the central portion of [Ahx5-17]NPY is characterized by relatively large loops. In contrast to previous models, practically no alpha-helical structure exists for these peptides under our conditions, but two beta-turns are found in NPY and one in [Ahx5-17]NPY. The proximity of the terminal ends could be the determinant factor for their activity.

Amino Acid Sequence↗
PubMed1995

Structural effects of the selective reduction of amide carbonyl groups in motilin 1-12 as determined by nuclear magnetic resonance.

Motilin is a 22-residue peptide stimulating stomach and intestinal motility. The motilin 1-12 fragment displays biological effects similar to the native peptide. Selective reduction of the amide carbonyl groups to form CH2NH analogs leads to a significant reduction in activity for the first two N-terminal positions and to a complete loss of activity for all other positions. The structures of motilin 1-12 and ten reduced analogs were investigated using the temperature dependence of the amide NH chemical shifts. In all the analogs, the structure of the N-terminal region (residues 1-5) was different from the structure of motilin 1-12, which is characterized by hydrogen bonding between Phe1 and Ile4. The structure of the C-terminal region of analogs was similar to the structure of motilin 1-12 for the first two reduction positions only (1-2 and 2-3), indicating that the C-terminal portion of motilin 1-12 is more critical for biological activity. Complete structural characterizations of motilin 1-12, [CH2NH]1-2, and [CH2NH]4-5-motilin 1-12 were performed by two-dimensional NMR spectroscopy and molecular modeling. The structural features observed confirm the differences based on the temperature dependence of the amide NH chemical shifts. These results demonstrate that conservation of the amide bond rigidity is essential for the activity of non-hydrolyzable analogs.

Amides↗
PubMed1995

Role of neuropeptide Y in the regulation of tyrosine hydroxylase gene expression in rat adrenal glands.

It is well known that the adrenal medulla contains high concentrations of neuropeptide Y (NPY) where it coexists with epinephrine and norepinephrine. In order to evaluate the possible involvement of NPY in the regulation of the chromafin cells of the rat adrenal medulla, we have studied the effects of NPY and some NPY analogs on the concentrations of tyrosine hydroxylase (TH) mRNA. The following peptides, NPY, PYY, [Leu31, Pro34]-NPY (a Y1 receptor agonist) and NPY13-36 (a Y2 receptor agonist) were administered intravenously at the dose of 40 micrograms/100 g body weight. All the animals were perfused with 4% paraformaldehyde 4 h after injection and cryostat sections of adrenals were processed for in situ hybridization using a 35S-labelled oligonucleotide probe encoding for rat TH. Optical density measurements performed in adrenal medulla demonstrated that the administration of NPY, PYY, and [Leu31, Pro34]-NPY induced a marked increase in the hybridization signal while the Y2 receptor agonist NPY13-36 did not affect TH mRNA levels. Then, these data clearly indicate that NPY positively regulates the genetic expression of TH probably via the Y1 NPY receptor subtype. They suggest that variations in the levels of circulating NPY or in the release of NPY by the chromaffin cells themselves (in autocrine and/or paracrine way) can increase the biosynthesis of catecholamines in rat adrenals.

Adrenal Medulla↗
PubMed1995

Characterization of neuropeptide Y binding sites in rat brain membrane preparations using [125I][Leu31,Pro34]peptide YY and [125I]peptide YY3-36 as selective Y1 and Y2 radioligands.

The peptide YY (PYY)-derivatives [Leu31,Pro34]PYY and PYY3-36 were respectively developed as selective Y1 and Y2 radioligands devoid of affinity for the Y3 receptor subtype. Each analog was iodinated by the chloramine T method after a purification by reverse-phase high-performance liquid chromatography. Both radioligands bind with high affinity, low capacity and in a time-dependent and saturable manner to specific sites present in rat frontoparietal cortical or hippocampal membrane preparations. [125I][Leu31,Pro34]PYY demonstrated apparent affinities (Kd) of 0.42 +/- 0.07 and 0.22 +/- 0.08 nM and maximal capacities (Bmax) of 185 +/- 14 and 33 +/- 4 fmol/mg of protein to a single class of sites in cortical and hippocampal membrane homogenates, respectively. Conversely, [125I]PYY3-36 apparently bound to a greater amount of sites in hippocampal (Bmax of 109 +/- 13 fmol/mg of protein; Kd of 0.13 +/- 0.03 mM) compared with cortical (Bmax of 33 +/- 5 fmol/mg of protein; Kd of 0.37 +/- 0.06 nM) membrane preparations, which suggests the differential enrichment of these two brain regions with a given neuropeptide Y (NPY) receptor subtype. The comparative ligand selectivity profile of these two radiolabeled PYY derivatives confirmed this hypothesis and revealed that, although the rat frontoparietal cortex is enriched with Y1 sites, Y2, receptor binding sites are most abundant in the hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Motilin synthetic analogues and motilin receptor antagonists.

While studying the structure-activity characteristics of motilin with motilin synthetic analogues, two compounds, motilin 1-12 [CH2 NH]3-4 and motilin 1-12 [CH2 NH]10-11, showed high affinity for the motilin receptor combined to a weak contractile activity. The following data suggest that motilin 1-12 [CH2 NH]10-11 is a potent motilin receptor antagonist. It showed a high affinity for the motilin receptor present on membranes of rabbit antrum (pIC50: 8.24 +/- 0.08 for the analogue vs 8.96 +/- 0.02 for the native peptide). When tested in vitro on strips of rabbit duodenum, the dose-response curve to motilin 1-22 was displaced to the right with motilin 1-12 [CH2 NH]10-11 (pIC50: 8.91 +/- 0.06 in presence of saline versus 7.19 +/- 0.40 with the analogue). However, when injected i.v. in dogs, motilin 1-12 [CH2 NH]10-11 was undetectable in the peripheral blood, suggesting enzymatic degradation precluding its use in vivo.

Animals↗
PubMed1994

Studies on the structure-activity of motilin in vivo. Effect of motilin synthetic analogues in conscious dog.

Synthetic analogues of motilin were tested for their capacity to stimulate the intestinal motor activity of the conscious dog. Physiological doses (75 pmol/kg) of motilin 1-22 and of motilin fragments 1-21, 1-20 and 1-19 induced premature periods of phase III activity in all tested animals. Motilin fragments 1-15, 1-12, 1-11 and 1-10 failed to influence the intestinal myoelectrical activity even when given at doses 10-times superior (750 pmol/kg). Motilin-like-immunoreactivity was measured in plasma during the analogues infusion. During the infusion of the bioactive analogues (1-22, 1-21, 1-20, 1-19), plasma motilin increased by 174 +/- 25 fmol/ml while a small rise (22 +/- 7.6 fmol) was noted with the inactive fragments (P < 0.001). Our data are in agreement with the in vitro findings that the N-terminal portion of the motilin molecule is responsible for its biological activity and suggests that the middle portion of the molecule is important to prevent degradation and maintain biological activity in vivo.

Animals↗
PubMed1994

Neurochemical effects of neuropeptide Y (NPY) and NPY2-36.

Our previous in vivo structure-activity studies suggested that the putative receptors mediating the effects of NPY and NPY2-36 on food intake and body temperature following ICV administration are pharmacologically different. In the present study, we examined and compared dose related effects of NPY and NPY2-36 on levels of norepinephrine (NE), dopamine (DA) and its main metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanilic acid (HVA), as well as serotonin (5-HT) and its metabolite, 5-hydroxyindolacetic acid (5-HIAA), in several brain regions of the rat, including: frontal cortex, hypothalamus, amygdala, septum, nucleus accumbens, corpus striatum, globus pallidus, substantia nigra and hippocampus. NPY and NPY2-36 (10 or 20 micrograms) were administered intraventricularly and the regional levels of the amines and metabolites were assessed 30 min following administration. Results indicate that both doses of NPY decreased NE levels within the hypothalamus. Furthermore, DOPAC concentrations were increased in this region while DA and HVA remained unchanged. The most pronounced neurochemical effects of NPY were found in the hippocampus, where the peptide produced dose related increases in DA, DOPAC and HVA. On the other hand, NPY2-36 significantly increased NE, DA and its metabolite DOPAC in both the amygdala and septum. The metabolism of DA was most obviously affected in the hippocampus and frontal cortex where levels of DA and DOPAC were significantly increased. 5-HT was affected in both the hypothalamus and globus pallidus where DA and its metabolite HVA were also increased.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Role of neuropeptide Y in the regulation of gonadotropin-releasing hormone gene expression in the rat preoptic area.

It is well documented that neuropeptide Y (NPY) is involved in the regulation of the hypothalamo-pituitary gonadal axis. In order to determine the influence of NPY on the biosynthesis of GnRH, we have studied the effects of NPY and some NPY analogs on GnRH gene expression in neurons in the male rat preoptic area (POA). The following peptides NPY, peptide YY (PYY), [Leu31,Pro34]NPY (a Y1 receptor agonist) and NPY13-36 (a Y2 receptor agonist) were injected into the left lateral ventricle of adult castrated male rats. In another series of experiments, the same peptides were administered intravenously (IV). All the animals were perfused with 4% paraformaldehyde 4 hours after injection. Cryostat sections through the POA were processed for quantitative in situ hybridization. The intracerebroventricular injection of PYY, NPY and [Leu31,Pro34]NPY induced a marked increase in the number of grains overlying the labelled neurons (20 to 45% over control). On the other hand, the Y2 receptor agonist NPY13-36 did not influence mRNA levels. Similar results were obtained following the i.v. administration although the magnitude of the stimulating effect was less important (12 to 20% over control). These data then strongly suggest that NPY positively regulates the genetic expression of GnRH in neurons via the Y1 NPY receptor subtype.

Animals↗
PubMed1994

Peptide YY derivatives as selective neuropeptide Y/peptide YY Y1 and Y2 agonists devoided of activity for the Y3 receptor sub-type.

Peptide YY derivatives were evaluated for their respective ability to bind and activate the NPY/PYY receptor sub-types (Y1, Y2 and Y3) present in various preparations. The analogue [Leu31,Pro34]PYY demonstrated high (nM) affinity in rat frontoparietal cortical membrane preparations (Y1-enriched tissue) and the rabbit saphenous vein (Y1 in vitro bioassay) but only low affinity in a Y2-enriched preparation (rat hippocampus). In contrast, PYY C-terminal fragments such as PYY3-36 and PYY13-36 were more potent in Y2 than Y1 assays. Interestingly, and in contrast to [Leu31,Pro34]NPY and NPY13-36, the PYY derivatives [Leu31,Pro34]PYY and PYY3-36 were inactive in a purported Y3 bioassay (rat colon). These results suggest that [Leu31,Pro34]PYY and PYY3-36 respectively represent the first selective and potent Y1 and Y2 agonists, devoided of significant affinity/activity for the Y3 receptor class.

Animals↗
PubMed1994

In vivo central actions of NPY(1-30), an N-terminal fragment of neuropeptide Y.

The purpose of the present study was to examine the possible central actions of a N-terminal fragment of NPY, NPY(1-30), on five measures typically influenced by the native peptide: decreased spontaneous activity, enhancement of muscle tone (increased grasping response), catalepsy, hypothermia, and stimulation of food intake. The peptides were administered ICV in doses ranging from 2.5 to 160 micrograms (0.75-48 nmol) and their effects on the three motor variables as well as thermal and feeding responses were evaluated and compared. Globally, results indicate that, similarly to NPY, the N-terminal fragment NPY(1-30), decreased spontaneous activity and induced hypothermia. However, the fragment displayed approximately half of the potency of NPY for producing these effects. On the other hand, contrary to NPY, NPY(1-30) did not affect muscle tone or food consumption and did not induced catalepsy in animals. These results demonstrate for the first time central actions of a N-terminal fragment of NPY and lend further support to the hypothesis that the receptors mediating the central actions of NPY are pharmacologically different.

Animals↗
PubMed1994

Autoradiographic distribution and receptor binding profile of [125I]Bolton Hunter-rat amylin binding sites in the rat brain.

Amylin is a recently isolated peptide from amyloid plaques in noninsulin-dependent diabetic patients and showed high sequence homology with calcitonin gene-related peptide. We investigated the distribution and the binding profile of [125I]Bolton Hunter-rat amylin ([125I]BH-rat amylin) binding sites in the rat brain, as well as the affinity of rat amylin for [125I]hCGRP alpha binding sites in the brain, atrium (CGRP1 receptor-enriched tissue) and vas deferens (CGRP2 receptor-enriched tissue). High amounts of high affinity [125I]BH-rat amylin binding sites were observed in the nucleus accumbens, various hypothalamic nuclei, amygdaloid body, dorsal raphe, tegmental and parabrachial nuclei and the locus ceruleus. Interestingly, both rat amylin and salmon calcitonin revealed low nanomolar affinities (2-19 nM) for [125I] BH-rat amylin binding sites in the various brain areas, whereas human calcitonin gene-related peptide-alpha (hCGRP alpha) showed lower affinities ranging between 13 to 150 nM. Moreover, the affinity of rat amylin was much lower than that of hCGRP alpha for [125I]hCGRP alpha binding in the brain, atrium and vas deferens, except for very few areas such as the nucleus accumbens and ventral striatum. Similarly, rat amylin was much weaker (100- to 400-fold) than hCGRP alpha to induce a biological effect in the atrium and vas deferens. These results thus suggest the existence of unique [125I]BH-rat amylin binding sites in the rat brain as well as limited cross-reactivity between rat amylin and [125I]hCGRP alpha receptors present in the brain, atrium and vas deferens.

Amyloid↗